BeatMG: Phase IITrial of Rituximab In Myasthenia Gravis

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government.
Read our disclaimer for details.

The specific primary objective of this study is to determine whether rituximab is a safe and beneficial therapeutic for Myasthenia Gravis (MG) that warrants further study in a phase III efficacy trial.

Condition or disease

Intervention/treatment

Phase

Myasthenia Gravis

Drug: RituximabDrug: Placebo

Phase 2

Detailed Description:

Investigators plan on conducting a multicenter randomized, double-blind, placebo controlled Phase II clinical trial utilizing a futility design. The study would include acetylcholine receptor (AChR) antibody positive generalized MG subjects. This study also presents a unique opportunity to study both drug and disease mechanisms because unlike many other autoimmune diseases in which rituximab has been used, MG affords the investigation of antigen-specific components that participate in the immunopathology of the disease, namely autoantibodies, autoantibody-producing B cells, and antigen-specific T cells. This work will further our understanding of MG immunopathology and it represents the first step toward gaining a more complete understanding of the immune mechanisms underlying treatment of MG with rituximab leading to new ways to treat the disease.

In order to assess safety in the B cell recovery during the repopulation period as well as the assess the long-term durability of response, there are two additional optional observational off study-intervention time points (weeks 72 and 96). The subjects will be treated per medical standard of care during this period.

The specific aim of this study is to determine whether rituximab is a safe and effective treatment for subjects with MG.

Intervention (rituximab): The treatment group will receive a total of two cycles of rituximab separated by 6 months. Each cycle is defined as one infusion (375mg/m2 IV) per week for four consecutive weeks

Drug: Rituximab

Intervention (rituximab): The treatment group will receive a total of two cycles of rituximab separated by 6 months. Each cycle is defined as one infusion (375mg/m2 IV) per week for four consecutive weeks

Percent of subjects that achieve a ≥ 75% reduction in mean daily prednisone dose in the 4 weeks prior to week 52 and do not worsen on the MGC (defined as a >2 increase from baseline at week 52) [ Time Frame: 4 weeks prior to week 52 ]

Frequency of Study-Related Adverse Events [ Time Frame: At the end of study-approximately 3 years ]

Secondary Outcome Measures :

Improvement in clinical outcome measure scores:Myasthenia Gravis Composite (MGC) [ Time Frame: At end of week 52 Treatment Period ]

Evaluate whether there is a trend towards clinical benefit at end of 52 week treatment period, as measured by MG-specific clinical outcomes scales used as endpoints in prior MG clinical trials

Improvement in clinical outcome measure scores: Quantitative Myasthenia Gravis(QMG) [ Time Frame: At end of week 52 Treatment Period ]

Evaluate whether there is a trend towards clinical benefit at end of 52 week treatment period, as measured by MG-specific clinical outcomes scales used as endpoints in prior MG clinical trials

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.

Ages Eligible for Study:

21 Years to 90 Years (Adult, Older Adult)

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

No

Criteria

Inclusion Criteria:

Subjects 21 to 90 years old

Subjects must have generalized MG, defined as MGFA clinical classification grades 2 (mild), 3 (moderate), or 4 (severe, but not intubated) at the time of screening/randomization.

Elevated AChR antibody titer

Subject's signs and symptoms should not be better explained by another disease process.

Subjects must be on a stable standard immunosuppressive regimen:

Prednisone only: Prednisone dose must be at least 15mg/day (or the equivalent on alternate days), and the dose of prednisone must have been stable for at least 4 weeks (28 days) prior to the baseline visit.

Prednisone plus another immunosuppressive therapy (IST). Immunosuppressive therapies other than prednisone, specifically azathioprine, mycophenolate mofetil, cyclosporine, tacrolimus or methotrexate, are permitted, but the dose must have been stable for at least 6 months prior to the baseline visit.

(Note: The prednisone dose must be stable as defined in the prednisone only group. The IST dose must remain stable throughout the course of the study).

Subjects must be willing to complete the study and return for follow-up visits.

No history of thymoma, tumor, infection, or interstitial lung disease on chest CT, MRI, or chest x-ray. Note: Chest x-ray will be completed at screening to look of interstitial lung disease. A chest CT or MRI to evaluate for thymoma must be completed as part of prescreening.

Able and willing to give written informed consent and comply with the requirements of the study protocol.

Subjects must be able to give written informed consent before participating in this study. A copy of the signed consent must be kept in the subject's medical record.

Men and women of reproductive potential must agree to use an acceptable method of birth control during treatment and for twelve months (1 year) after completion of treatment.

Exclusion Criteria:

A history of chronic degenerative, psychiatric, or neurologic disorder other than MG that can produce weakness or fatigue.

Other major chronic or debilitating illnesses within six months prior to study entry.

Subjects who have been medicated with immunosuppressive drugs not listed in inclusion #5 within the last 8 weeks (56 days) prior to the baseline visit

Subjects who have been medicated with an immunosuppressive agent such as azathioprine, mycophenolate mofetil, cyclosporine, tacrolimus or methotrexate, that is withdrawn within 8 weeks (56 days) of the Baseline Visit.

Subjects who have received IVIg or PLEX treatment within the last 4 weeks (28 days) prior to the baseline visit.

Unstable dose or a stable dose of > 480 mg/day of pyridostigmine in 2 weeks prior to screening visit.

Daily use of non-steroidal anti-inflammatory drugs (NSAIDs).

History of renal or hepatic insufficiency or elevated liver enzymes (AST or ALT >2.5 x Upper Limit of Normal).

History of positive HIV (HIV conducted during screening if applicable)

Treatment with any investigational agent within 4 weeks of screening or 5 half-lives of the investigational drug (whichever is longer)

Receipt of a live vaccine within 4 weeks prior to randomization

Previous treatment with rituximab (MabThera® / Rituxan®)

Previous treatment with natalizumab (Tysabri®)

History of severe allergic or anaphylactic reactions to humanized or murine monoclonal antibodies

History of recurrent significant infection or history of recurrent bacterial infections

Known active bacterial, viral fungal mycobacterial, or other infection (including tuberculosis or atypical mycobacterial disease, but excluding fungal infections of nail beds) or any major episode of infection requiring hospitalization or treatment with IV antibiotics within 4 weeks of screening or oral antibiotics within 2 weeks prior to screening

Unstable steroid dose in the past 4 weeks (28 days)

Lack of peripheral venous access

History of drug, alcohol, or chemical abuse within 6 months prior to screening

Concomitant malignancies or previous malignancies, with the exception of adequately treated basal or squamous cell carcinoma of the skin or carcinoma in situ of the cervix or prostate.

History of psychiatric disorder that would interfere with normal participation in this protocol

Any other disease, metabolic dysfunction, physical examination finding, or clinical laboratory finding giving reasonable suspicion of a disease or condition that contraindicates the use of an investigational drug or that may affect the interpretation of the results or render the subject at high risk from treatment complications

Subjects that do not record daily prednisone doses for at least 28 days before the Baseline Visit, or subjects whose prednisone dose varies by ≥6mg/day on average.

Prednisone dose of more than 100 mg/day (or 200 mg over a two day period).